Skeletal muscle fatigue and post-exertional malaise are key symptoms of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (ME/CFS). We have previously shown that AMP-activated protein kinase ...(AMPK) activation and glucose uptake are impaired in primary human skeletal muscle cell cultures derived from patients with ME/CFS in response to electrical pulse stimulation (EPS), a method which induces contraction of muscle cells
The aim of the present study was to assess if AMPK could be activated pharmacologically in ME/CFS. Primary skeletal muscle cell cultures from patients with ME/CFS and healthy controls were treated with either metformin or compound 991. AMPK activation was assessed by Western blot and glucose uptake measured. Both metformin and 991 treatment significantly increased AMPK activation and glucose uptake in muscle cell cultures from both controls and ME/CFS. Cellular ATP content was unaffected by treatment although ATP content was significantly decreased in ME/CFS compared with controls. Pharmacological activation of AMPK can improve glucose uptake in muscle cell cultures from patients with ME/CFS. This suggests that the failure of EPS to activate AMPK in these muscle cultures is due to a defect proximal to AMPK. Further work is required to delineate the defect and determine whether pharmacological activation of AMPK improves muscle function in patients with ME/CFS.
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in the Western world and the incidence of the disease is constantly increasing. Most patients with NAFLD do not present ...with symptoms directly attributable to their underlying liver disease. It is increasingly recognized, however, that those with NAFLD describe a range of non-specific symptoms, which include fatigue and daytime sleepiness, may be the presenting problem and can impact dramatically upon quality of life in this patient group. The recognition of systemic symptoms in NAFLD has important implications for patients as many are potentially modifiable with targeted interventions. Fatigue appears to be a significant problem in NAFLD and the severity of fatigue is not associated with severity of NAFLD or any parameters of liver damage. Instead, fatigue in these patients shows a strong relationship with the symptom of daytime sleepiness and autonomic dysfunction. Daytime sleepiness can frequently be associated with obstructive sleep apnoea in those with NAFLD and is therefore treatable with evidence-based interventions. Recent studies have confirmed the presence of autonomic nervous system dysfunction in those with early stages of NAFLD. The presence of autonomic nervous system dysfunction leads to symptoms such as postural dizziness and syncope and is also associated with a number of clinical consequences in hepatic and non-hepatic diseases such as cognitive dysfunction, falls and fall-related injuries. On direct questioning, problems with memory and concentration are frequently described by those with NAFLD, with our studies confirming that 50% of NAFLD patients experience mild cognitive symptoms and up to 46% moderate or severe cognitive impairment. There were no positive correlations between cognitive symptoms and biochemical or histological markers of liver damage severity, confirming that cognitive impairment in early-stage NAFLD is not related to hepatic encephalopathy. Falls are also considered a direct consequence of autonomic nervous system dysfunction, and our work suggests that a history of falls is common in NAFLD (43%). The proportion of recurrent fallers is significantly higher in a NAFLD cohort compared to controls (p = 0.001), with injuries (p = 0.009), emergency medical attention (p < 0.001), fracture rates (p < 0.001) and hospital admission (p < 0.001) all significantly more common in the NAFLD group. Falls and the aforementioned associations were unrelated to the presence of diabetes or the severity of liver disease. A range of systemic symptoms appear to affect those with NAFLD, the severity of which is unrelated to the underlying liver disease severity. The presence of autonomic dysfunction may provide a unifying mechanism for these symptoms and a therapeutic target. Consideration of these symptoms affecting patients with NAFLD and, where possible, effective treatment will lead to improvements in quality of life and enhance the ability of those with NAFLD to function in their daily lives.
Chronic fatigue syndrome (CFS) patients often suffer from severe muscle pain and an inability to exercise due to muscle fatigue. It has previously been shown that CFS skeletal muscle cells have lower ...levels of ATP and have AMP-activated protein kinase dysfunction. This study outlines experiments looking at the utilisation of different substrates by skeletal muscle cells from CFS patients (n = 9) and healthy controls (n = 11) using extracellular flux analysis. Results show that CFS skeletal muscle cells are unable to utilise glucose to the same extent as healthy control cells. CFS skeletal muscle cells were shown to oxidise galactose and fatty acids normally, indicating that the bioenergetic dysfunction lies upstream of the TCA cycle. The dysfunction in glucose oxidation is similar to what has previously been shown in blood cells from CFS patients. The consistency of cellular bioenergetic dysfunction in different cell types supports the hypothesis that CFS is a systemic disease. The retention of bioenergetic defects in cultured cells indicates that there is a genetic or epigenetic component to the disease. This is the first study to use cells derived from skeletal muscle biopsies in CFS patients and healthy controls to look at cellular bioenergetic function in whole cells.
A large body of evidence has established a pattern of altered functioning in the immune system, autonomic nervous system and hypothalamic pituitary adrenal axis in chronic fatigue syndrome. However, ...the relationship between components within and between these systems is unclear. In this paper we investigated the underlying network structure of the autonomic system in patients and controls, and a larger network comprising all three systems in patients alone.
In a sample of patients and controls we took several measures of autonomic nervous system output during 10 minutes of supine rest covering tests of blood pressure variability, heart rate variability and cardiac output. Awakening salivary cortisol was measured on each of two days with participants receiving 0.5mg dexamethasone during the afternoon of the first day. Basal plasma cytokine levels and the in vitro cytokine response to dexamethasone were also measured. Symptom outcome measures used were the fatigue impact scale and cognitive failures questionnaire. Mutual information criteria were used to construct networks describing the dependency amongst variables. Data from 42 patients and 9 controls were used in constructing autonomic networks, and 15 patients in constructing the combined network.
The autonomic network in patients showed a more uneven distribution of information, with two distinct modules emerging dominated by systolic blood pressure during active stand and end diastolic volume and stroke volume respectively. The combined network revealed strong links between elements of each of the three regulatory systems, characterised by three higher modules the centres of which were systolic blood pressure during active stand, stroke volume and ejection fraction respectively.
CFS is a complex condition affecting physiological systems. It is important that novel analytical techniques are used to understand the abnormalities that lead to CFS. The underlying network structure of the autonomic system is significantly different to that of controls, with a small number of individual nodes being highly influential. The combined network suggests links across regulatory systems which shows how alterations in single nodes might spread throughout the network to produce alterations in other, even distant, nodes. Replication in a larger cohort is warranted.
Introduction. Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a debilitating disorder of unknown aetiology, characterised by severe disabling fatigue in the absence of alternative ...diagnosis. Historically, there has been a tendency to draw psychological explanations for the origin of fatigue; however, this model is at odds with findings that fatigue and accompanying symptoms may be explained by central and peripheral pathophysiological mechanisms, including effects of the immune, oxidative, mitochondrial, and neuronal pathways. For example, patient descriptions of their fatigue regularly cite difficulty in maintaining muscle activity due to perceived lack of energy. This narrative review examined the literature for evidence of biochemical dysfunction in CFS/ME at the skeletal muscle level. Methods. Literature was examined following searches of PUB MED, MEDLINE, and Google Scholar, using key words such as CFS/ME, immune, autoimmune, mitochondria, muscle, and acidosis. Results. Studies show evidence for skeletal muscle biochemical abnormality in CFS/ME patients, particularly in relation to bioenergetic dysfunction. Discussion. Bioenergetic muscle dysfunction is evident in CFS/ME, with a tendency towards an overutilisation of the lactate dehydrogenase pathway following low-level exercise, in addition to slowed acid clearance after exercise. Potentially, these abnormalities may lead to the perception of severe fatigue in CFS/ME.
To describe physical activity (PA) levels and motivators and barriers to PA amongst haemodialysis (HD) patients and to identify an appropriate approach to increasing their PA.
A cross-sectional mixed ...methods study conducted in a tertiary and satellite HD unit. One hundred and one participants aged 18 years and over, receiving regular HD for at least four months, were recruited. Patients with recent hospital admission or acute cardiac event were excluded. Participants completed health status (EQ-5D-3L™) and activity (Human Activity Profile (HAP)) questionnaires. A subgroup was invited to wear accelerometers and wearable cameras to measure PA levels and capture PA episodes, to inform subsequent semi-structured interviews on motivators and barriers. Semi-structured interviews were analysed using the framework method informed by constructs of the Health Belief Model.
98/101 completed the study (66 males, 32 females). For 68/98 participants, adjusted activity scores from the HAP indicated "impaired" levels of PA; for 67/98 participants, the EQ-5D-3L indicated problems with mobility. Semi-structured interviews identified general (fear of falls, pain) and disease specific barriers (fatigue) to PA. Motivators included tailored exercise programmes and educational support from health care professionals.
Participants indicated a need for co-development with healthcare professionals of differentiated, targeted exercise interventions.
Implications for rehabilitation
Healthcare professionals should encourage and motivate haemodialysis patients to participate in physical activity (PA).
As part of this approach, there is a need to increase patient knowledge of safe beneficial exercise activities and help individuals identify and overcome barriers.
To allow for individualised approaches, clinical interventions should focus on other community activities that patients can do outside the dialysis clinic setting and utilise existing networks such as the British Renal Society Rehabilitation Network.
The dialysis clinic provides professionals the opportunity to monitor and motivate patients.
Relevant education is needed for staff about the benefits of PA and how to engage patients and their carers in safe and effective approaches.
Background
Osteoarthritis (OA) is a chronic joint disease, with increasing global burden of disability and healthcare utilisation. Recent meta-analyses have shown a range of effects of OA on ...mortality, reflecting different OA definitions and study methods. We seek to overcome limitations introduced when using aggregate results by gathering individual participant-level data (IPD) from international observational studies and standardising methods to determine the association of knee OA with mortality in the general population.
Methods
Seven community-based cohorts were identified containing knee OA-related pain, radiographs, and time-to-mortality, six of which were available for analysis. A two-stage IPD meta-analysis framework was applied: (1) Cox proportional hazard models assessed time-to-mortality of participants with radiographic OA (ROA), OA-related pain (POA), and a combination of pain and ROA (PROA) against pain and ROA-free participants; (2) hazard ratios (HR) were then pooled using the Hartung–Knapp modification for random-effects meta-analysis.
Findings
10,723 participants in six cohorts from four countries were included in the analyses. Multivariable models (adjusting for age, sex, race, BMI, smoking, alcohol consumption, cardiovascular disease, and diabetes) showed a pooled HR, compared to pain and ROA-free participants, of 1.03 (0.83, 1.28) for ROA, 1.35 (1.12, 1.63) for POA, and 1.37 (1.22, 1.54) for PROA.
Discussion
Participants with POA or PROA had a 35–37% increased association with reduced time-to-mortality, independent of confounders. ROA showed no association with mortality, suggesting that OA-related knee pain may be driving the association with time-to-mortality.
Funding
Versus Arthritis Centre for Sport, Exercise and Osteoarthritis and Osteoarthritis Research Society International.
Chronic fatigue syndrome (CFS) is characterised by a constellation of symptoms diagnosed with a number of different polythetic criteria. Heterogeneity across these diagnostic criteria is likely to be ...confounding research into the as-yet-unknown pathophysiology underlying this stigmatised and debilitating condition and may diagnose a disease spectrum with significant implications for clinical management. No studies to date have objectively investigated this possibility using a validated measure of CFS symptoms-the DePaul Symptom Questionnaire (DSQ).
To examine whether current CFS diagnostic criteria are identifying different disease phenotypes using the DSQ.
Case control study.
Clinical Research Facility of the Royal Victoria Infirmary, Newcastle upon Tyne, UK.
49 CFS subjects and ten matched, sedentary community controls, excluded for co-morbid depression.
Self-reported autonomic and cognitive features were assessed with the Composite Autonomic Symptom Score (COMPASS) and Cognitive Failures Questionnaire (COGFAIL) respectively. Objective autonomic cardiovascular parameters were examined using the Task Force® Monitor and a battery of neuropsychological tests administered for objective cognitive assessment.
Self-reported autonomic and cognitive symptoms were significantly greater in CFS subjects compared to controls. There were no statistically significant differences in objective autonomic measures between CFS and controls. There were clinically significant differences between DSQ subgroups on objective autonomic testing. Visuospatial memory, verbal memory and psychomotor speed were significantly different between DSQ subgroups.
The finding of no significant differences in objective autonomic testing between CFS and control subjects may reflect the inclusion of sedentary controls or exclusion for co-morbid depression. Consistent exclusion criteria would enable better delineation of these two conditions and their presenting symptoms. Findings across CFS subgroups suggest subjects have a different disease burden on subjective and objective measures of function, autonomic parameters and cognitive impairment when categorised using the DSQ. Different CFS criteria may at best be diagnosing a spectrum of disease severities and at worst different CFS phenotypes or even different diseases. This complicates research and disease management and may contribute to the significant stigma associated with the condition.
Fatigue is a significant symptom that is frequently reported by those with postural tachycardia syndrome (PoTS). There are a variety of reasons why those with PoTS might experience fatigue and as a ...consequence an individualised approach to management is most appropriate.
In this chapter we will examine the prevalence of fatigue in those with PoTS, its overlap with conditions such as chronic fatigue syndrome and describe a clinical approach to the management of fatigue in those with PoTS.
•Fatigue is a common symptom described by those with PoTS.•Chronic Fatigue Syndrome is often co-diagnosed with PoTS.•Management of fatigue in PoTS is best delivered as a multidisciplinary approach.
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is a rare disease with no known etiology. It affects 0.4% of the population, 25% of which experience the severe and very severe categories; ...these are defined as being wheelchair-, house-, and bed-bound. Currently, the absence of biomarkers necessitates a diagnosis by exclusion, which can create stigma around the illness. Very little research has been conducted with the partly defined severe and very severe categories of CFS/ME. This is in part because the significant health burdens experienced by these people create difficulties engaging in research and healthcare provision as it is currently delivered. This qualitative study explores the experiences of five individuals living with CFS/ME in its most severe form through semi-structured interviews. A six-phase themed analysis was performed using interview transcripts, which included identifying, analysing, and reporting patterns amongst the interviews. Inductive analysis was performed, coding the data without trying to fit it into a pre-existing framework or pre-conception, allowing the personal experiences of the five individuals to be expressed freely. Overarching themes of 'Lived Experience', 'Challenges to daily life', and 'Management of the condition' were identified. These themes highlight factors that place people at greater risk of experiencing the more severe presentation of CFS/ME. It is hoped that these insights will allow research and clinical communities to engage more effectively with the severely affected CFS/ME population.
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